The rate at which pharmaceutically active compounds dissolve in gastrointestinal fluids is of crucial importance in the design and use of orally administered medications. The active compound must be dissolved before it can be absorbed by the body. The rate at which the active substance enters into solution is know in the art as the dissolution rate, and the determination of the dissolution rate in vitro is known as dissolution testing.
The concept of using in vitro data to predict or model in vivo behavior, referred to as in vitroxe2x80x94in vivo correlation, or IVIVC, is of great interest to the pharmaceutical arts. Test methods with good IVIVC are much more capable of detecting problems with existing formulations and in the development of new formulations. Systems which correlate closely with the dissolution and absorption data obtained in vivo can be used in developing dosage forms as well as in the production, scale-up, determination of lot-to-lot variability, testing of new dosage strengths, testing of minor formulation changes, testing after changes in the site of manufacture and for determining bio-equivalence.
Various methods and devices for dissolution measurement are well known and described in the art.
The US Food and Drug Administration (US FDA) has issued guidelines on the levels of correlation that are more or less desirable in in vitro testing (Guidance for Industry, Extended Release Oral Dosage Forms: Application of In vitro/In vivo Correlations, September 1997). A Level A correlation is one that predicts the entire in vivo time course from the in vitro data. A Level B correlation is one that uses statistical moment analysis. The mean dissolution time is compared either to the mean residence time or to the mean in vivo dissolution time. A Level C correlation establishes a single point relationship between a dissolution parameter and a pharmacokinetic parameter. Level B and Level C correlations do not reflect the complete shape of the plasma concentration-time curve. A Multiple Level C correlation relates in vitro data at several time points to several pharmacokinetic parameters. It is generally considered that if a multiple level C is possible, then Level A correlation should also be possible. Rank order correlations are those where only a qualitative relationship exists between in vitro and in vivo.
A Level A correlation is considered to be the most informative and is recommended by the USFDA wherever possible. Multiple Level C correlations can be as useful as Level A, but a Level A is preferred. Single point Level C correlations are considered useful only in the early stages of formulation development. Level B correlations are the least useful for regulatory purposes. Rank order correlations are not considered useful for regulatory purposes.
Having a high level of correlation, eg Level A, can reduce the amount of in vivo testing necessary for new formulations and can therefore be very valuable to pharmaceutical companies.
The US Pharmcopeia (USP24, pages 1941-1951) describes seven different sets of apparatus for performing dissolution testing. Apparatus 1 and 2 in section  less than 711 greater than  (pages 1941-1942) are essentially containers with a suitable stirring device into which is placed a fixed volume of dissolution medium, and the formulation being tested. Samples of the medium are withdrawn at various times and analyzed for dissolved active substance to determine the rate of dissolution. Section  less than 724 greater than  (pages 1944-1951) describes various apparatus designed to test dissolution of extended release, delayed release, and transdermal delivery systems. Apparatus 3 (extended release) uses a reciprocating cylinder, Apparatus 4 (extended release) uses a flow-through cell, Apparatus 5 (transdermal) utilizes a paddle over a disk, Apparatus 6 (transdermal) uses a cylinder design, and Apparatus 7 (transdermal) uses a reciprocating holder. Apparatus 1, 2, 3, 5, 6, and 7 use a fixed volume of the dissolution medium. Apparatus 4 uses a continuous flow of dissolution medium. In all cases the volume of dissolution medium used is sufficient to completely dissolve the test substance, frequently known as sink conditions.
For many active substances and dosage forms the principles behind the USP dissolution tests are limiting. These limitations are true for those active substances for which the rate of dissolution is dependent upon the amount of said active substances already dissolved in the release medium. These include, but are not limited to complexes between active substances and ion exchange resins, and poorly soluble active substances. Some combinations of ion exchange resin and active substances form an equilibrium state under fixed volume conditions such that some of the drug remains on the resin, even at infinite time and under sink conditions. This will give rise to incomplete dissolution when using test methods similar to those described in USP24. When an active substances has been dissolved in the gastrointestinal system it is absorbed by the body through the walls of the gastrointestinal system. This results in a decrease in the concentration of the active substance in solution. In the case where the active substance is in equilibrium with the polymeric complex, as described above, this decrease in concentration will displace the equilibrium such that more active substance will be released. As absorption by the body continues, the release of drug from the polymeric complex will be essentially complete. It is therefore clear that the in vitro test as described above, indicating incomplete release, is not predictive of the release in vivo. A similar deficiency will occur with poorly soluble materials when sink conditions do not occur in vivo. The concentration will reach saturation, and the dissolution rate will then depend on the rate of absorption of the active substance by the body. The fixed volume limitation does not apply to the flow-through equipment (Apparatus 4 as described in USP24). In this case the test material is constantly exposed to fresh dissolution medium, where the concentration of active substance is always zero. While this eliminates the equilibrium constraint, and therefore does permit the complete dissolution of such active substances, it still does not simulate the physiological condition where the concentration of active substance is zero only at the start. With formulations controlled by equilibrium or limited solubility it is clear to one skilled in the art that the USP methods cannot be expected to give good IVIVC without further mathematical manipulation of the data. In the current art, Level A IVIVC is obtained by the use of mathematical tools to convert the in vitro data into predicted plasma concentration curves, or similar pharmacokinetic data that reflect the entire time course of the drug in the body. While this is acceptable to the regulatory authorities it is not completely satisfactory because any mathematical model involves basic assumptions, and a major change in a formulation, for example release mechanism or change in solubility, may render those assumptions invalid, requiring the use of a different mathematical model. This limits the predictive power of the IVIVC.
The use of a mathematical model to transform the data is also not ideal because it is not immediately apparent from the raw data obtained in the dissolution test if a change has been significant. It is necessary to transform the data using the model before the effect of the change can be evaluated. The value of a mathematical model is frequently related to the number of independent variables used to adjust the model to fit the in vivo data. As a guideline the USFDA recommends no more than three independent variables.
The conditions that affect dissolution in the gastro-intestinal system are known to vary with position within the gastro-intestinal system. These variations can affect the rate of dissolution of active substances. There have been attempts to simulate these changes in in vitro testing. The main focus has been on the very large pH change between the stomach and upper GI. This change is large enough to have a very serious effect on the solubility of some active substances. For example, diclofenac sodium is essentially insoluble at the low pH of the stomach, but is soluble at the near neutral conditions of the upper GI. In the current art this change of pH has been addressed in two ways. The first has been to change the fluid used in the dissolution test, for example start with gastric fluid and then change to intestinal fluid. The second has been to change the pH gradually by addition of a higher pH solution. Neither of these methods adequately simulates the pH change in vivo because in both methods all the formulation experiences the pH change at the same time, whereas in vivo the pH change is controlled by gastric emptying which causes a gradual transfer of the disintegrated formulation so that different portions of the formulation experience the pH changes at different times. In U.S. Pat. No. 5,807,115 Hu states that it is difficult to move an already disintegrated solid sample. Hu uses this conclusion to justify the gradual change of pH described above.
A method that has been used to solve the problem associated with the USP fixed volume and flow-through methods has been the continuous flow cell in which either the contents of the cell is stirred, or a part of the effluent is recycled to the cell. This allows equilibrium effects to be evaluated.
The equipment described by Huynh-Ngoc and Sirois (J. Pharm Belg, 1976, 31, 589-598; ibid 1977, 32, 67-75) is a continuous flow apparatus. The equipment was designed to facilitate replacement of gastric fluid with intestinal fluid to simulate the transit of the test material through the gastrointestinal system. The authors establish only a rank order VIVC. Takenaka, Kawashima and Lin (J. Pharm Sci, 69, 1388-1392, 1980) describe an apparatus similar in form to that of Huynh-Ngoc and Sirois. The authors made no connection between their data and in vivo performance, although it is clear to one skilled in the art that the limitations will be the same as those for the Huynh-Ngoc and Sirois equipment. Pernarowski, Woo, and Searl (J. Pharm Sci, 57, 1419-1421, 1968) also report the use of a continuous flow method. The authors do make comparison of their results with in vivo performance but it is only a rank order correlation.
The equipment described by Archondikis and Papaioannou (International Journal of Pharmaceutics, 1989, 55, 217-220) is a flow-through cell like the USP Apparatus 4 but returned the fluid removed from the vessel to the fresh fluid reservoir, such that the fluid was continuously recirculated from the reservoir to the flow-through cell and back to the reservoir. This arrangement results in a fixed volume test, the limitations of which have been described above. The equipment described by Miller, Maikner, and Hickey (Am. Chem. Soc, Div. Polym. Chem), 33, 82-83, 1992) is of the flow through type. It has the same limitations regarding IVIVC as does the USP Apparatus 4 described above.
In U.S. Pat. No. 4,335,438 Smolen describes a combination of a flow-through cell with recycle and a mathematical model. The mathematical model is used in conjunction with varying the test parameters to optimize said parameters to give a predicted in vivo plasma curve from the in vitro data. pH change is possible, but it is the same method as used by Hu, and suffers the same limitations. The number of independent variables used is very high. There are four basic variables, flow rate, amount of recycle, pH, and stirring rate. In addition, it is necessary to vary these with time so that the number of possible combinations of variables is essentially infinite. The results obtained using the invention potentially represent a Level A correlation, but based on USFDA guidelines the number of independent variables is too great and so this is not an acceptable model for establishing IVIVC. It is also clear to one skilled in the art that it is possible with this invention to create test parameters that are not physiologically relevant. Regulatory agencies and the USP guidelines strongly recommend that dissolution conditions be physiologically relevant.
In all of the flow-through systems described above only one cell is used per test. There are multiple cell systems available commercially, but these have multiple cells in parallel so that each cell is independent of the other and hence they are a plurality of single cell systems.
Dissolution testing provides a better understanding of the amount of a pharmaceutically active compound available at a particular absorption site at various times. In addition, establishing a relationship between dosage form and availability of a pharmaceutically active compounds at certain absorption sites and systemic blood levels of such active compound aids in the development of specialized delivery techniques.
Dissolution technology that allows determination of IVIVC for pharmaceutically active compounds that exist in complexes wherein the active substance is bound to a solid or other particulate material and exists in a state of equilibrium with the surrounding medium has not yet been developed. Previous techniques for correlating in vitro and in vivo dissolution data have been limited to accounting for such factors as interactions with salts, enzymes, the ionic strength and pH of the medium and temperature. Discrepancies between in vitro and in vivo values of dissolution and absorption have previously been corrected for by transformation of data such as by applying intestinal weighting functions, which transformations may not allow for physiological interpretation.
Thus, there is a need for an integrated assessment of in vitro dissolution of a pharmaceutical formulation and absorption of an active compound from such formulation. Previously these parameters have been considered separately. With the development of more advanced dosage forms, especially for formulations that provide a delayed release of compound, better predictive models are necessary.
Also, there is need for an in vitro dissolution test that takes into account the absorption of the active substance by the body and the presence of dissolved active substance during the dissolution.
Further, there is also a need for an in vitro dissolution test that is able to demonstrate Level A IVIVC without the need for mathematical models to transform the in vitro data. Additionally, there is also a need for an in vitro test that gives data directly comparable with in vivo data without the need for mathematical models to transform the in vitro data.
Finally, there is also need for an in vitro test that can be used with different dosage forms of the same active ingredient that gives Level A IVIVC for other dosage forms without the need for different test conditions for each dosage form.
Surprisingly, Applicant has invented an apparatus and a test method that satisfies all these needs.
The following terms have the following meanings herein:
The terms xe2x80x9cmediumxe2x80x9d, xe2x80x9cmediaxe2x80x9d, or xe2x80x9crelease mediumxe2x80x9d as used herein, means the liquid medium into which the active substance is being released. Examples of release media can be water, simulated intestinal fluid, simulated gastric fluid, simulated saliva, or the authentic physiological versions of these fluids, water, and various buffer solutions.
The term xe2x80x9cresidence timexe2x80x9d as used herein, is a well known engineering concept applied to continuous flow systems, and is calculated by mathematically dividing the volume of liquid in a vessel by the flow rate into an out of the vessel such that the volume of liquid remains constant. For example, a flow rate of 5 ml/min into and out of a vessel containing 10 ml of liquid has a residence time of 2 minutes.
The term xe2x80x9cresinatexe2x80x9d as used herein, means the product derived from forming a complex between an ion exchange resin and an ionizable organic compound.
The term xe2x80x9cdosage form,xe2x80x9d xe2x80x9csample,xe2x80x9d xe2x80x9ccomposition,xe2x80x9d xe2x80x9cagent,xe2x80x9d xe2x80x9ccompoundxe2x80x9d, or xe2x80x9csubstancexe2x80x9d as used herein, means a chemical, a material, a composition, a blend, or a mixture of materials or components that will at least partially dissolve within a release medium to release an active agent. The terms characteristics, parameters, and specifications may be used interchangeably herein and are intended to refer to some property, ingredient, quantity, quality, etc. of a composition or dosage form.
The term xe2x80x9cCmaxxe2x80x9d as used herein, means the maximum concentration observed in the blood plasma concentration vs time curve for in vivo data, or the cell effluent concentration vs time curve for in vitro data.
The term xe2x80x9ctmaxxe2x80x9d as used herein, means the time taken to reach Cmax after the administration of the drug, either in vivo, or in vitro.
The term xe2x80x9ct10xe2x80x9d as used herein, means the time taken after the occurrence of Cmax for the concentration to fall to 10% of the value of Cmax.
The term xe2x80x9cgastric chamberxe2x80x9d as used herein, refers to the first of three chambers of the current invention, the design and function of which is described hereinbelow.
The term xe2x80x9cintestinal chamberxe2x80x9d as used herein, refers to the second of three chambers of the current invention, the design and function of which is described hereinbelow.
The term xe2x80x9ccirculatory chamberxe2x80x9d as used herein, refers to the third of three chambers of the current invention, the design and function of which is described hereinbelow.
The terms xe2x80x98release profilexe2x80x99 and xe2x80x98dissolution profilexe2x80x99 as used herein, mean the change in concentration with time of the substance being tested.